CCN1 accelerates re-epithelialization by promoting keratinocyte migration and proliferation during cutaneous wound healing

Highlights: • Re-epithelialization is the restoration of skin integrity following injury. • CCN family member 1 (CCN1) is upregulated in the early stages following injury. • CCN1 promotes human primary keratinocyte migration and proliferation. • Topical CCN1 application stimulates re-epithelialization in mouse burn models. • CCN1 is more potent than bFGF in initiating re-epithelialization. Re-epithelialization is an essential part of wound healing and has a prominent influence on the prognosis. CCN family member 1 (CCN1 or Cysteine-rich 61, CYR61), a matricellular protein, has a potential role in the wound healing process. However, its role in re-epithelialization remains unclear. The aim of this study was to determine the expression of CCN1 in the epidermis and its effect on keratinocytes during re-epithelialization. CCN1 expression in the wounded skin was analyzed using microarray data from GEO database and detected by immunofluorescence. The results showed upregulated CCN1 during the early stages of wound healing. Human primary keratinocytes were treated with recombinant human CCN1. The results showed that CCN1 promoted keratinocyte migration and proliferation. Moreover, a full-thickness mouse skin wound model and a superficial second-degree burn mouse model treated intracutaneously with CCN1 were used for in vivo studies. Topical treatment with CCN1 protein accelerated wound closure and re-epithelialization. Additionally, longer newly-formed epithelium tongue and elevated expression of PCNA and Ki67 were detected in the CCN1-treated group 4 days post-burn. These results indicate that CCN1 accelerates re-epithelialization by promoting keratinocyte migration and proliferation, and may serve as a novel target to promote re-epithelialization.